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Fibroblast Growth Factor Receptors (FGFRs) are a family of receptor tyrosine kinases expressed on a plethora of cell membranes. They play crucial roles in both embryonic development and adult tissue functions. There is an increasing amount of evidence that FGFR-mediated oncogenesis is mainly related to gene amplification, activating mutations, or translocation in tumors of various histological types. Dysregulation of FGFRs has been implicated in a wide variety of neoplasms, such as bladder, gastric, and lung cancers. Given their functional significance, FGFRs emerge as promising targets for cancer therapy. Here, we introduce CPL304100, an innovative and highly potent FGFR1-3 kinase inhibitor demonstrating excellent in vitro biological activity. Comprehensive analyses encompassed kinase assays, cell line evaluations, PK/PD studies surface plasmon resonance studies, molecular docking, and in vivo testing in mouse xenografts. CPL304110 exhibited a distinctive binding profile to FGFR1/2/3 kinase domains, accompanied by a good safety profile and favorable ADMET parameters. Selective inhibition of tumor cell lines featuring active FGFR signaling was observed, distinguishing it from cell lines lacking FGFR aberrations (FGFR1, 2, and 3). CPL304110 demonstrated efficacy in both FGFR-dependent cell lines and patient-derived tumor xenograft (PDTX) in vivo models. Comparative analyses with FDA-approved FGFR inhibitors, erdafitinib and pemigatinib, revealed certain advantages of CPL304110 in both in vitro and in vivo assessments. Encouraging preclinical results led the way for the initiation of a Phase I clinical trial (01FGFR2018; NCT04149691) to further evaluate CPL304110 as a novel anticancer therapy., Competing Interests: DP, AM, MS, JH-K, DS, MD, FM, WP, AY, and KDu are employees at Celon Pharma SA. AS, JP, JD, PS, KJ, KDz, ML-P, and DZ-B were employees at Celon Pharma SA, MW is the owner and CEO of Celon Pharma SA. AY, AS, DZ-B, KDz, KDu, MW, ML-P, PS are authors of patent applications. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Popiel, Stańczak, Skupińska, Mikołajczyk, Stańczak, Mituła, Hucz-Kalitowska, Jastrzębska, Smuga, Dominowski, Delis, Mulewski, Pietruś, Zdżalik-Bielecka, Dzwonek, Lamparska-Przybysz, Yamani, Olejkowska, Piórkowska, Dubiel, Wieczorek and Pieczykolan.)